chr16-4823850-C-T

Variant names:

• chr16-4823850-C-T
• rs1372957638
• NM_032569.4:c.595G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_032569.4(GLYR1):​c.595G>A​(p.Ala199Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,613,906 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A199V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GLYR1 NM_032569.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.861
• Publications: 0 publications found

Genes affected

GLYR1 (HGNC:24434): (glyoxylate reductase 1 homolog) Enables DNA binding activity; methylated histone binding activity; and nucleosome binding activity. Involved in positive regulation of histone acetylation and positive regulation of transcription by RNA polymerase II. Located in cytosol and nucleoplasm. Part of nucleosome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.035188794).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032569.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLYR1	NM_032569.4	MANE Select	c.595G>A	p.Ala199Thr	missense	Exon 6 of 16	NP_115958.2
	GLYR1	NM_001308096.2		c.595G>A	p.Ala199Thr	missense	Exon 6 of 16	NP_001295025.1	Q49A26-3
	GLYR1	NM_001324098.2		c.595G>A	p.Ala199Thr	missense	Exon 6 of 15	NP_001311027.2	Q49A26-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLYR1	ENST00000321919.14	TSL:1 MANE Select	c.595G>A	p.Ala199Thr	missense	Exon 6 of 16	ENSP00000322716.6	Q49A26-1
	GLYR1	ENST00000591451.5	TSL:1	c.595G>A	p.Ala199Thr	missense	Exon 6 of 16	ENSP00000468328.1	Q49A26-3
	GLYR1	ENST00000589389.5	TSL:1	c.556G>A	p.Ala186Thr	missense	Exon 5 of 14	ENSP00000466570.1	K7EMM8

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152038 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461868 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727232

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111994

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152038 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74260

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41390

American (AMR) AF: 0.00 AC: 0 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10584

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2088

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	10
DANN	Uncertain	0.98
DEOGEN2	Benign	0.033	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.035	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.86
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.36	N
REVEL	Benign	0.029
Sift	Benign	0.46	T
Sift4G	Benign	0.68	T
Polyphen		0.010	B
Vest4		0.23
MutPred		0.23		Gain of glycosylation at A199 (P = 0.0247)
MVP		0.21
MPC		0.019
ClinPred		0.13	T
GERP RS		0.012
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.020
gMVP		0.24
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1372957638; hg19: chr16-4873851;